Amyloid-beta (Abeta) peptides can induce NF-kappaB-dependent production of inflammatory cytokines, nitric oxide (NO) and superoxide in microglia. Expression of endogenous anti- inflammatory agents such as heat shock protein 70, glucocorticoids and glucocorticoid receptor, which mediate some of their actions by attenuating NF-kappaB activity, is increased by caloric restriction (CR). To determine if CR can attenuate Abeta-induced cytotoxicity and inflammation by modulating NF- kappaB activity, amyloid-derived diffusible ligands (ADDLs) will be infused into the lateral ventricle, and the rat brains will be assayed for expression of inflammatory cytokines, apoptosis, and translocation of NF-kappaB to nucleus. The proposed experiments will also examine if CR modulates transcription of NF-kappaB/Rel proteins. ADDLs-induced activation of microglia from young ad libitum (AL), middle-aged CR and middle-aged AL rats will be assessed in vitro by secretion of inflammatory cytokines and NO. The role of NF-kappaB in this response will be determined by reporter gene expression and by inhibition of cytokine and NO production by lipofection of "decoy" kappaB binding site. Collectively, these studies will assess the impact of diet on molecular mechanisms that may exacerbate progression of Alzheimer's disease.